The molecular targets for photoreceptor degenerations and uveitis (intraocular inflammation) are poorly understood. A major barrier to progress has been the lack of any specific molecular cause. This proposal builds on our exciting discovery of calcium-activated CAPN5 (calpain-5) as the cause of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). CAPN5 is the first nonsyndromic uveitis gene, and makes possible a highly innovative molecular-genetic approach for mechanism-based therapies for inflammation induced by photoreceptor degeneration. Photoreceptors express CAPN5, and an hCAPN5- R243L gain of function mutation in mice shows all the phenotypes of human ADNIV disease. The retina photoreceptors might be particularly sensitive to mutations in CAPN5, because high intracellular calcium is necessary and sufficient to regulate dark adaptation in photoreceptors. Our long-term goals are to find better and more specific treatments for photoreceptor degeneration. Our objective is to use our new hCAPN5-R243L mice to determine whether blocking CAPN5 activity can inhibit degeneration and uveitis. Our central hypothesis is that a calcium-activated CAPN5 pathway leads to ADNIV retinal degeneration and uveitis, and our transgenic CAPN5 mutant mouse is the best available animal model for testing several new uveitis therapies. Our specific aims are to (1) Treat photoreceptor degeneration in hCAPN5-R243L mice with a pharmacological CAPN5 inhibitor, (2) Rescue the photoreceptor phenotype in hCAPN5-R243L mice with a novel bipartite shRNA gene silencing vector, and (3) Treat uveitis in hCAPN5-R243L mice using commercially available neutralizing antibodies targeting IL-6 and IL-23. Impact. We expect to establish the hCAPN5-R243L mouse as a valuable animal model for testing novel therapies in ADNIV, which can be translated to patients. Our work should help determine the role of of calcium-activated CAPN5 signaling in ADNIV and other photoreceptor degenerations. Since hCAPN5-R243L disease stages phenocopy other eye diseases with photoreceptor degeneration and components of the CAPN5 pathway are found in other forms of uveitis, our studies could have a broad, positive impact, beyond ADNIV and uveitis patients, where components of the CAPN5 pathway may be therapeutic targets.